Gender differences in expression of drug transporter genes in human livers: Microarray and real-time PCR analysis

B34

Membrane transporters and ion channels are encoded by numerous gene families. These genes code for a number of proteins involved in many physiologic processes, such as lipid transport, sterol homeostasis, immune mechanisms and drug transport. Gender differences in adverse drug reactions have been reported with a number of chemotherapeutic drugs suggesting a possible role for drug transporters. Using Illumina Human Whole-Genome beadchips (Human-6-v1), males (50) and females (52) age- matched liver samples were analyzed for differentially expressed genes according to gender. Microarray filtered analysis identified 1,640 genes differentially expressed according to gender. Of the 1,640 genes, 26 were molecular transporters. Seventeen genes from the solute carrier (SLC) family (SLC30A1, 43A1, 31A2, 31A1, 35F5, 43A1, 4A1AP, 5A10, 5A6, 6A16, 9A1, 10A1,16A11, 22A12, 22A2, 22A9 25A13 and SLCO1B1) and three from the ATP-binding (ABC) family (ABCA5, ABCB6 and ACCN4) were differentially expressed between genders. Other transporters that were differentially expressed were OST beta, ATP7B, KCNK5, TRPC4AP, KCNJ8 and ATP2B2. Real-time PCR analyses validated the microarray results and further showed, in addition to expression by gender, intra-individual differences within gender. The ABC and SLC transporters mediate energy-dependent drug efflux and uptake, therefore playing a major role in chemoresistance and pharmacokinetic disposition of drugs. Gender differences in adverse reactions to certain drugs could be attributed to differences in transporters expression. Knowledge of gender differences in expression may, thereby, be a key component in ensuring optimal patient outcome.